Chief of the Early Drug Development Service Alexander Drilon says targeted therapies can help some patients achieve a "Lazarus effect" — dramatic improvement when they've run out of other options.
“We’ve seen sick patients who were practically knocking on death’s door,” says Alexander Drilon, Chief of Memorial Sloan Kettering’s Early Drug Development (EDD) Service. “Targeted therapy then achieved a Lazarus effect — their cancer-related symptoms dramatically improved, and they went back to living their lives the way they did prior to their cancer diagnosis.”
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In just the past three years, the US Food and Drug Administration has approved three drugs developed by the EDD and Dr. Drilon’s team, working with pharmaceutical companies. In May 2020, selpercatinib (Retevmo™) was approved to treat lung and thyroid cancers driven by RET fusions or mutations. In August 2019, entrectinib (Rozlytrek™) was approved for lung cancer driven by ROS1 fusions and all cancers driven by NTRK fusions. In November 2018, larotrectinib (Vitrakvi®) was approved for adult and pediatric tumors driven by NTRK fusions. All of these drugs are targeted therapies, which block the cancer-causing genes and directly attack tumors while mostly sparing healthy cells.
Doctors in the EDD Service specialize in developing new therapies for cancers, including those with specific gene changes. “Immunotherapy can work extremely well for some cancers,” Dr. Drilon says, adding that his patients often ask if these drugs are an option. “But for cancers caused by a mutation or fusion, targeted therapy can work much better.” Unlike therapies that activate the immune system to fight the cancer, targeted therapy drugs like selpercatinib, entrectinib, and larotrectinib turn off the signals that tell cancer cells to grow and divide.
A Second Chance for a Born Teacher
Florida grandmother and retired middle school music teacher Melissa Crouse is one of the patients whose life was turned around by Dr. Drilon’s work.
When Melissa met Dr. Drilon for the first time in April 2017, she’d been living with lung cancer for 12 years and had been through five other clinical trials. “None of them worked well, but together they kept me alive,” she says. “Then I learned about the trial at MSK.”
I don’t think I’d still be here today without it,” says patient and advocate Melissa Crouse about a targeted drug she received in a clinical trial at MSK.
That June, Melissa received her first dose of selpercatinib, taken as a pill. By September, a scan showed her tumors were shrinking. The extreme fatigue she felt in the beginning subsided. She has had no evidence of disease since April 2020. She continues to take the pill every day and is amazed to feel so well.
“Selpercatinib was my sixth clinical trial,” says 66-year-old Melissa. “I don’t think I’d still be here today without it.”
“Melissa’s experience was remarkable,” says Lauren Kaplanis, a clinical trials nurse who works with Dr. Drilon. “And it was repeated in many of the nearly 100 people we’ve treated with this drug so far.”
“We’ve known about the link between RET fusions and lung cancer since 2011, but prior to the start of the selpercatinib trial in 2017, there were no drugs that were designed to optimally target only the RET protein,” Dr. Drilon says. Other drugs were less effective and caused a lot more side effects.
The New Frontier
RET fusions or mutations are one of many gene changes targeted by a new class of more powerful drugs. The genes affected by these changes sound like an alphabet soup — EGFR, ALK, ROS1, NTRK — but in this exciting era of molecular testing and personalized medicine, they’ve become common lingo for patients. Melissa even started a group called the “RET Renegades” for others with RET fusions or mutations. Changes in RET and hundreds of other cancer-causing genes can be detected with MSK-IMPACT™, a diagnostic test developed at MSK.
Dr. Drilon is not the only specialist at MSK focused on targeted therapies for lung cancer. In September 2020, physician-scientists Piro Lito and Bob Li reported dramatic results in the New England Journal of Medicine from the first-ever clinical study of a drug that targets a common mutation in a gene called KRAS. KRAS mutations are found in about one quarter of lung cancers, and until recently they were considered to be “undruggable” mutations because of the shape of the KRAS protein.
In January 2021, Dr. Li reported at the World Conference on Lung Cancer Presidential Symposium that in the registrational phase II trial, 100 of 126 patients whose cancer was caused by a KRAS mutation called KRAS-G12C had their tumors either shrink or stop growing. Of those, 46 patients’ tumors shrank substantially, and half of them were still responding to the drug ten months later. Nine people had to stop taking the drug because of side effects. Based on these results, the FDA designated sotorasib a Breakthrough Therapy.
“Sotorasib is the first among a growing number of emerging therapeutics aiming to directly target KRAS-mutant cancers,” says Dr. Lito, who is a member of the Thoracic Oncology Service and the Human Oncology and Pathogenesis Program.
“Sotorasib is not a cure, but this study is the first to crack KRAS in a clinically meaningful way,” adds Dr. Li, a member of the EDD and Thoracic Oncology Services. Dr. Li and Dr. Lito are continuing to study sotorasib in clinical trials.
Expanding Access Beyond Clinical Trials
Philanthropy has provided critical support for the investigators in the EDD Service. The Fiona and Stanley Druckenmiller Center for Lung Cancer Research at MSK provided funding for Dr. Drilon’s research with RET gene changes, among other important work, as well as Dr. Li’s research.
“Through the EDD Service, we are able to offer select patients outcomes with targeted therapy that they may never attain with other standard therapies. I have patients who have taken these drugs for years and are still doing well,” Dr. Drilon says. “When these drugs are approved by regulatory agencies around the world, more people can access these new treatments.” Other pathbreaking work in the EDD Service has also received support from Mike Repole and his Nonna’s Garden Foundation.
For Dr. Drilon and his team, there is no greater motivation. Their work has made a difference not only for his own patients and those being treated by the EDD Service — it’s changing therapies for cancer patients everywhere.
Melissa is now an activist and patient advocate, even starring in an Emmy Award-winning documentary about lung cancer called Melissa’s Story.
A self-described type A personality, she had left her teaching job when she started the selpercatinib trial. She says, “If I had known then what I know now, I wouldn’t have retired.”
